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Cell Biology International (2003) 27, 1–6 (Printed in Great Britain)
Extending the ‘stressy’ edge: molecular chaperones flirting with RNA
Tamás Henics*
Department of Molecular Biology, INTERCELL, Biomedical Research and Development AG, Campus Vienna Biocenter 6, Vienna 1030, Austria


Abstract

A number of intriguing observations have emerged during the past years indicating that certain classes of the evolutionarily highly conserved heat shock or stress proteins extend their molecular partnerships beyond the originally recognized protein world. In this review, following a brief introduction to the 70-kDa family of stress proteins, we summarize the main aspects of RNA recognition and binding by this class of molecules. By highlighting some biochemical features of both the protein and RNA partners, we attempt to embed the central parts of this interaction in the context of potential physiological relevance. As perhaps true for many newly recognized molecular interactions, the phenomenon of RNA recognition and binding by molecular chaperones discussed in this review calls for a place of ever-growing importance in the functional genomic era, where an expanding number of previously unsuspected molecular partnerships are uncovered by virtue of powerful high throughput methodologies. We suggest that integration of this new knowledge into the long-outlined ‘classical’ network of cellular metabolism at both the biochemical and architectural level is pivotal to the emerging ‘synthesis era’ of today's cell biology.


Keywords: Heat shock protein, Molecular chaperone, RNA-binding, AU-rich elements, RNA–protein interaction, mRNA metabolism.

*Tel.: +43-1-20-620-210; fax: +43-1-20-620-800


1 The 70-kDa stress proteins

A long-recognized phenomenon in cell physiology is that in response to a wide range of environmental conditions, such as hyperthermia, oxidative stress, osmotic disturbances or nutrient withdrawal, living cells express a set of proteins, known as heat shock or stress proteins (hsps) (for review, see Black and Subjeck, 1991; Welch et al., 1982). Among the most prominent hsps (28, 60, 70, 90 and 110kDa in mammalian cells), the 70-kDa species appears as a doublet (approximately 72 and 73kDa) known as hsp70 (a major inducible homologue in most organisms) and hsc70 (cognate or constitutive), respectively. While both of these hsp70s are cytoplasmic, other hsp70 family members are found in every major sub-cellular compartments of eukaryotic cells, as seen, for example, with BiP (also called Grp78), an exclusive endoplasmic reticulum-resident homologue. A striking primary amino acid sequence homology of over 60% identifies these proteins among the most conserved gene products in biology (Hunt and Morimoto, 1985).

One finds hsp70 family members conducting essential regulatory activities in a variety of cellular mechanisms that have been detailed elsewhere (Beckmann et al., 1990; Chappell et al., 1986; Chiang et al., 1989; Chirico et al., 1988; Flynn et al., 1989; Nelson et al., 1992). The ultimate biological task behind this functional diversity, in virtually every domain of cellular life, is for hsps to assist in the maintenance of a wide variety of cellular processes. This assistance extends to survey the conformational integrity of complex protein structures and their components and to protect and restore damaged structures imposed by harmful and usually proteotoxic environmental conditions. A common theme in these activities is the ability of hsp70s to recognize and bind to normally unexposed hydrophobic peptide stretches within their substrate proteins, thus, stimulating the evolvement of functionally active conformations (Bukau and Horwitz, 1998; Hartl, 1996; Johnson and Craig, 1997). The chaperone–substrate interaction occurs in an ATP-regulated manner and hsps also accept the catalytic assistance of so-called co-chaperone molecules, such as DnaJ or hsp40, for eukaryotic hsp70 during the chaperone cycle (for review see Hendrick and Hartl, 1993; Ohtsuka and Hata, 2000). The molecular pre-requisite of chaperone–substrate interactions is the unique domain composition of the chaperone molecule. The corresponding sequence of different family members can be quite variable (e.g. between hsp70 and hsp110; Easton et al., 2000; Lee-Yoon et al., 1995), but confer a similar secondary structure, giving rise to the N-terminal ATPase domain (five-stranded antiparallel β-sheet enclosed by α-helices on both surfaces forming an ATP-binding cleft), followed by a peptide-binding β-sheeted domain and the C-terminal alpha-helical regulatory region (also referred to as a ‘lid’) (Oh et al., 1999; Zhu et al., 1996).

2 The story of molecular chaperone–RNA interactions

In the early 1980s, when, other than their sub-cellular distribution, not much was known about the function of hsps in general, a number of observations suggested that under both normal and elevated temperatures, the ubiquitous stress proteins may associate with a number of molecular components of the cell, most importantly with the subject of this review, the RNA (Loetzel and Bautz, 1983). The rapid expansion of research in-line with the molecular chaperoning concept (McKay et al., 1994; Rassow et al., 1997), together with the nearly simultaneous acceleration of the RNA metabolism field, particularly those of translation and mRNA turnover, exposed the evidence indicating that certain stress proteins may directly or indirectly interact with various RNA species in a diverse array of organisms. For example, GroEL, the Escherichia coli hsp60 homologue has been identified within a protein complex that protects bacterial transcripts from RNase E-mediated degradation (Georgellis et al., 1995; Sohlberg et al., 1993) and was later demonstrated to co-purify with the bacterial degradosome, a complex assembly of regulated RNA decay in prokaryotes (Miczak et al., 1996). Most importantly, DnaK, the E. coli hsp70 homologue was also shown to be part of the same complex (Miczak et al., 1996). Intriguing as they were, yet, these studies did not demonstrate direct RNA-binding by hsps or their functional involvement in specific RNA metabolism. The first such direct evidence came with the identification of the 60-kDa chaperonin (hsp60 homologue) of the thermophilic archaeon, Sulfolobus solfataricus as an interacting partner of the 16S rRNA, specifically required to cleave the rRNA precursor at a specific 5′ site (Ruggero et al., 1998). Additionally, an hsp101 homologue, conserved throughout in higher plants, has been shown to exhibit direct binding to the 5′ leader sequence of tobacco mosaic virus acting as a translational enhancer (Wells et al., 1998). Importantly, this newly recognized function was also found in yeast and was independent of the thermoprotective role of the chaperone (Wells et al., 1998). Another direct RNA-binding role was clearly assigned to a yeast hsp40 homologue with its demonstration as a nuclear tRNA-binding protein (Wilhelm et al., 1994). This same homologue was later proposed to readily associate with ribosomes—partly via its direct interaction with ribosomal RNA—and function together with Ssb, a ribosome-associated yeast hsp70 homologue (Pfund et al., 1998; Yan et al., 1998). Finally, a new ribosome-associated 15-kDa hsp was recently identified in E. coli, with high-affinity RNA-binding capacity via its novel RNA-binding domain (Korber et al., 1999; Korber et al., 2000; Staker et al., 2000). Together, these results paved the way for research directly addressing RNA-binding by members of certain hsp families.

Earlier results of label transfer (UV cross-linking) experiments from a number of laboratories have identified RNA–protein complexes with sizes of 40, 60, 70 or 100kDa (Henics et al., 1994; Malter, 1989). For example, using various cell extracts, such as those of human lymphocytes, and labeled AU-rich 3′UTR RNAs of various lymphokine and proto-oncogene mRNAs (Chen and Shyu, 1995; Ross, 1995), a complex, nearly 70kDa, was frequently demonstrated (Henics et al., 1994; Soós et al., 1998). Direct analysis of mammalian hsp/hsc70 proteins and of the more distantly related family member, hsp110, in label transfer assays confirmed the direct RNA-binding by thesemolecules (Henics et al., 1999). Studies addressing the in vitro RNA-binding sequence preference of human hsp70 and hsc70 proteins using different RNA probes, as well as various homoribopolymers, in competition experiments showed that hsps do not bind RNA indiscriminately. Instead, AUUUA motif-containing 3′UTR destabilizing elements (widely referred to as ARE) (Chen and Shyu, 1995), as well as poly(U) stretches, also found within the 3′UTR of a number of mRNAs, are the primary RNA targets for hsps (Henics et al., 1999; Zimmer et al., 2001). Similar RNA-binding properties were recently demonstrated for BiP, the endoplasmic reticular hsp70 homologue (Zimmer et al., 2001).Immunoprecipitation of hsp70 from protein–RNA complexes of human lymphocyte proteins and AU-rich RNA probes (Henics et al., 1999) provided the initial clues that hsp-RNA complexes may also form in vivo.

The first hint on the identity of the RNA-binding region was obtained using various deletion mutants of hsp110 (Henics et al., 1999; Oh et al., 1999). These results demonstrated that the RNA-binding segment of the molecule resides within the N-terminus and is identical with the nucleotide (ATP)-binding domain, a finding that was also made more recently for hsp70 (Zimmer et al., 2001). The C-terminal structures of the chaperone were not involved directly in RNA-binding, but were suggested to transmit sterical (structural) and/or functional information for the N-terminal ATP-binding domain with possible modulatory role in RNA-binding. More recent work has shown that the N-terminal 44-kDa ATPase domain of hsp70 is itself sufficient to bind RNA, and that the previously seen RNA sequence specificity was lost if the inter-domain communication of the ATPase domain with C-terminal residues was perturbed (Zimmer et al., 2001). Together, these results further supported the assumption that the C-terminal portions of the molecule are required to fine-tune the RNA-binding properties of the N-terminal domain (for details see Zimmer et al., 2002). Such transmission of regulatory information between various domains has been described in classical studies where chaperoning function of DnaK, Ssa/Ssb (yeast hsp70 homologues) and hsp70 was analyzed and dramatic re-arrangements of chaperone structure upon binding of a peptide substrate are indicated (Buchberger et al., 1995; Davis et al., 1999; James et al., 1997; Liberek et al., 1991; Lopez-Buesa et al., 1998). It was, therefore, proposed that these intra-molecular conformational changes might, in part, share some similarities with those observed in the RNA-binding assays with mutant hsps or in the presence of a peptide substrate and ATP (Henics et al., 1999; Zimmer et al., 2001). Consistent with this view was the finding that the co-chaperones DnaJ and GrpE both have modulator effects on the RNA-binding activity of DnaK in an in vitro re-constituted chaperone cycle (Zimmer et al., 2001). Finally, Wilson et al. characterized in detail the thermodynamics of hsp70 interaction with the ARE of tumor necrosis factor,α mRNA, and showed that a highly dynamic complex with 1:1 stoechiometry of RNA to protein forms as a result of a high-affinity binding event. The phenomenon is independent of the folding state of the RNA and is co-operative in the presence of polyuridylate as an RNA-binding partner, suggesting—in agreement with earlier data—that U-rich RNA is sufficient for RNA-recognition and binding by hsp70 (Wilson et al., 2001).

3 Provoking observation or relevant physiological function?

Currently, the exact physiological role of AU-rich RNA-binding by the members of the 70-kDa chaperone family in cellular RNA metabolism is not known. Earlier cases of such molecular promiscuity, as seen with aconitase or GAPDH, demonstrate that the same protein with different function can operate in distant molecular compartments (Klausner and Rouault, 1993; Nagy and Rigby, 1995). With the current detailed information on RNA-binding by hsp70 and other family members, it is possible to speculate on a number of possibilities as to how this novel molecular interaction may integrate into various elements of cytoplasmic RNA metabolism (also see Fig. 1). One possibility is that hsp70 interacts with various ARE-containing mRNAs in conjunction with other known ARE-binding proteins (AU-rich sequence binding proteins, AUBP), either competing directly for ARE or binding independently to modulate RNA conformation and, thus, affecting binding by other proteins. For example, hsp70 has been shown to regulate complex formation between the 3′UTR of erythropoietin (Epo) mRNA and its specific binding protein, ERBP (Scandurro et al., 1997).Hypoxia induces binding of ERBP to Epo mRNA and stabilizes the message, whereas sequestration of ERBP by hsp70 under norm-oxic (non-stress) conditions prevents such complex formation that leads to rapid degradation of Epo mRNA (Scandurro et al., 1997). An even more relevant sequestration phenomenon involves AUF1, an indispensable factor for ARE-mediated mRNA degradation. Elimination of AUF1 by an ubiquitination-coupled degradosomal activity is necessary for AU-rich RNA decay, and prevention of this process, as well as heat shock, leads to nuclear–perinuclear sequestration of AUF1 by hsp70 and, consequently, to suspension of AUF1 and mRNA degradation (Laroia et al., 1999).


Fig. 1

Illustration of putative functions by members of the 70-kDa chaperone family in various processes of cytoplasmic mRNA metabolism. Hsps70 and 110 bind AU-rich 3′UTR destabilizing sequences in vitro and are implicated in direct binding to various mRNAs to facilitate functionally active RNA conformations (direct RNA chaperoning function) or possibly stabilize ribosome complexes while acting as nascent peptide-binding chaperones. Hsp70 family members may also be involved in activating functional AUBP conformations or sequester and release certain AUBPs in a regulated manner. Central to hsp function is the ATP/ADP and co-chaperone (DnaJ/GrpE) assisted binding of a protein/peptide substrate (S) (encircled in gray) that has been shown to affect in vitro RNA-binding by chaperones. Dynamic conformational transitions and interactions between the main domains of hsp70/110 (N-terminal ATPase domain, substrate-binding domain, SBD and the C-terminal lid structure) may have crucial regulatory roles in the functional commitment of the chaperones in their diverse biological functions.


Two pertinent observations came from the yeast, Sacharomyces cerevisiae. Analysis of a newly identified regulator of the yeast decapping enzyme, Dcp1p, revealed that mutation of this protein results in the reduction of decapping activity and an increased mRNA stability. Interestingly, enhanced interaction of the abundant yeast hsp70 homologue, Ssa/2p, was demonstrated with Dcp1p in cell extracts of mutant strains in decapping activity, suggesting that this yeast hsp70 homologue may be involved in the regulation of mRNA decapping and consequently in mRNA stability (Zhang et al., 1999). Another study showed that mRNAs encoding for an insulinase-like endoprotease, Axl1p, are less abundant and stable in mutants strains for Ydj1p, a yeast homologue of the hsp40 co-chaperone (Meacham et al., 1999). Since Ydj1p acts to regulate Ssa protein function, these authors suggest that modulation of mRNA stability by the yeast hsp70/hsp40 system may operate in regulating the expression of certain protein factors at the post-transcriptional level.

Another possible domain of hsp involvement in RNA metabolism is mRNA translation (see Fig. 1). As nascent chain-binding chaperones, hsp70 homologues have been located on polysomes in both yeast and mammalian cells (Beck and De Maio, 1994; Nelson et al., 1992; Pfund et al., 1998). Moreover, re-evaluation of the sub-cellular location of zuotin, a novel yeast DnaJ co-chaperone, revealed that this molecule also binds to ribosomes (Yan et al., 1998). Recently, in connection with its modulatory activity on the α sub-unit of eukaryotic initiation factor 2 (HRI), hsc70 has also been linked to the translation complex (Uma et al., 1999). We propose that hsp/hsc70 and hsp110 molecules not only assist in co- and post-translational folding of newly synthesized polypeptides, but also potentiate translational activity by directly chaperoning mRNA molecules and/or assisting in the assembly of RNA–protein complexes to modulate localization or stability of the transcripts. Results demonstrating that interaction of Sis1, the essential hsp40 homologue of S. cerevisiae, with the Ssa hsp70 homologue and Pab1 (poly(A)-binding protein) is required for translation (Horton et al., 2001) provide strong credit to such proposal. In the light of these data, we propose a complementary function for hsp/hsc70 protein pools in which a dynamic re-compartmentalization of pre-existing chaperones would assist in the protection and folding assistance of macromolecular sub-sets as diverse as proteins or RNAs (see also Zimmer et al., 2002).

4 Discoveries to come—concluding remarks

With the aid of wide-scale genomic information, cell biology has entered an integrative phase, where both existing and newly discovered molecular interactions have been subjected to revised interpretation. New levels of supra-molecular interactions and organization will, therefore, be extremely valuable building blocks in better understanding as to how metabolic pathways function and interact. Because of the vast diversity of their functions, molecular chaperones, in general, and the members of the hsp70 family, in particular, have long been central to establishing a comprehensive functional network, and indeed, research in the past years in this area has largely changed the view on this remarkable class of molecules (see also Csermely, 2001). Central to this review, an exciting new perspective will be to understand how the general stress sensor and protection mechanisms are coordinately regulated in both the signal receiving and responsive ends. It will be fundamental to decipher the integrative elements of these mechanisms and see as to what extent proteins and other macromolecules, such as RNA are involved. An important set of studies has identified highly conserved regions (HCRs) within 3′UTR sequences of certain messages that are sensitive to oxidative and mitogenic stress (Spicher et al., 1998). As elevated expression of hsps also coincides with such conditions, it will be important to test if stress proteins could also serve as sensors via direct RNA-binding to HCRs, and thus through modulating the expression of relevant gene products at the mRNA level or, alternatively, by protecting such RNA species during otherwise deleterious conditions.

Finally, we believe that further characterization of the mechanisms of RNA recognition and binding by molecular chaperones will identify as yet unsuspected layers of complexity in macromolecular interactions within the cell. Thus, addressing the questions as to what are the RNA species that associate with hsps in vivo, what are the main structural characteristics of hsp–RNA complexes, how co-chaperones are involved in the regulation of RNA-binding by the principal hsp molecule, or whether, as long proposed, but never addressed (Brennecke et al., 1998; DiDomenico et al., 1982; Kaarniranta et al., 1998; Lee, 1998; Moseley et al., 1993; Simcox et al., 1985; Theodorakis and Morimoto, 1987; Yost et al., 1990), hsps are involved in the regulation of stability, localization and/or translation of their own mRNAs will all contribute to the better understanding of general stress-related molecular events at the whole-cell level.

Acknowledgements

This work was partly supported by funds from the Wiener Wirtschaftsförderungsfond and theForschungförderungsfond.

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Received 19 February 2002; accepted 31 October 2002

doi:10.1016/S1065-6995(02)00286-X


ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
Published by Portland Press Limited on behalf of the International Federation for Cell Biology (IFCB)